INTERLEUKIN-1-BETA REGULATES PITUITARY FOLLISTATIN AND INHIBIN ACTIVIN BETA(B) MESSENGER-RNA LEVELS AND ATTENUATES FSH-SECRETION IN RESPONSE TO ACTIVIN-A/

Activins and follistatins regulate all levels of the reproductive axis , including the pituitary where they stimulate and inhibit FSH product ion, respectively. Gonadotropes are known to express inhibin/activin b eta(B) and activin-B (beta(B)beta(B)) functions as an autocrine modula tor of FSH production. By contrast, the mRNA for the activin-binding p rotein, follistatin, is present in most pituitary cells and folliculo- stellate cells may be the major source of the protein secreted by the anterior pituitary. Interleukin-1 beta (IL-1 beta) is one of several c ytokines known to also influence the reproductive axis. IL-1 beta inhi bits the hypothalamo-pituitary-gonadal (HPG) axis by suppressing GnRH and gonadal steroid production. Because several pituitary cell types, including follistatin-producing folliculo-stellate cells, are targets of IL-1 beta, cytokine effects on gonadotrope function were evaluated using cultured rat anterior pituitary cells. Activin-A (0.01 to 1 nM; 24h) increased basal FSH secretion similar to 2-fold. IL-1 beta (0.005 to 0.5 nM) by itself had no effect on basal FSH secretion. However, I L-1 beta attenuated FSH secretion in response to all concentrations of activin-A. These results suggest that the cytokine might stimulate th e local production of a factor, such as follistatin, that antagonizes the action of activin-A. RNase protection analysis indicated that IL-1 beta (0.005 to 5 nM) stimulated follistatin and inhibin/activin PB mR NA accumulation in a time-dependent manner. These in vitro effects of IL-1 beta were blocked by the specific IL-1 receptor antagonist (IL-1r a) and were not mimicked by either rhIL-6 or lipopolysaccharide (LPS). Treatment of intact male rats with LPS (50 mu g, iv), which increases plasma IL-1 beta and induces IL-1 beta expression in many tissues, in cluding the pituitary, produced similar time-dependent increases in pi tuitary follistatin and inhibin/activin subunit mRNA levels. These res ults suggest that IL-1 beta can modulate gonadotrope responses to acti vins by influencing the local balance of activin-B and follistatin wit hin the pituitary.